Alphavirus interactions with cellular receptors are likely to play a major role determining viral tropism and driving virus-induced disease. However, the viral receptors that mediate alphavirus entry are poorly understood. A genome wide screen using Sindbis virus identified NRAMP as a potential alphavirus entry receptor in insect cells. Additional studies suggest that NRAMP is also an entry receptor for Venezuelan Equine Encephalitis virus. Furthermore, in mammalian cells the ubiquitously expressed homolog, NRAMP2, can mediate infection of these alphaviruses. Our long-term goal is to dissect the role of NRAMPs in infectivity and pathogenesis of alphaviruses with the goal of developing strategies to combat these pathogens. We will study this important interaction by dissecting the determinants on NRAMPs that mediate binding and entry. Furthermore, we will sequence NRAMP from different enzootic and epizootic hosts to determine whether polymorphisms impact virus infection. We will take advantage of powerful assays that we have developed to study alphavirus entry and infection both in insect and mammalian cells to explore the role of NRAMPs in viral infection. Our central hypothesis is that dissecting the interactions of these medically important arboviruses with their receptor will reveal mechanisms that will aid in the development of antiviral treatments against these understudied pathogens for which there are no vaccines or therapeutics.